PROJECT DESCRIPTION- Heterotrimeric G proteins are signaling switches primarily activated by membrane receptors of the GPCR superfamily, the targets for >30% of FDA-approved drugs. However, we have recently discovered a GPCR-independent mechanism of heterotrimeric G protein activation that “rewires” this signaling pathway to regulate multiple cellular processes and diseases. Our research has direct implications in cancer cell biology, embryonic development and neurotransmission.
The primary project of the successful candidate will consist of characterizing and optimizing a newly identified small molecule inhibitor that blocks a GPCR-independent mechanism of G protein signaling and has anti-metastatic properties. This will involve biochemical analysis of compounds generated by chemist collaborators at our institution, and detailed studies on the cell biological consequences of the action of such compounds. Progressively, the potential anti-metastatic therapeutic activity of these compounds will also be investigated in mouse models.
In addition, it is also expected that the applicant will participate in related secondary projects and collaborative projects within and/or outside our laboratory.
QUALIFICATIONS REQUIRED- We are looking for candidates with a recent Ph.D. and experience in Cell Biology and Biochemistry, as demonstrated by a strong publication record. Prior knowledge of GPCR/G protein signal transduction is preferred but not essential. We are looking for motivated and creative individuals with a commitment to academic research who can work independently as well as in team-based projects. Good oral and written communication skill are a must.
The atmosphere in the laboratory is collaborative and multidisciplinary. The successful candidate will interact on a daily basis with colleagues carrying out studies on different areas of research (cancer, development, neurobiology) and approaches (purified proteins, structural biology, primary and cell line cultures, BRET, mice, frogs, etc). Our laboratory is highly committed to the career development of trainees.
The Department of Biochemistry at Boston University offers a highly collegial atmosphere and a first rate research environment.
SKILLS: Experience with several of the techniques listed below is expected:
Cellular and Molecular Biology: Cell culture, confocal and live cell fluorescence microscopy, molecular cloning, genetic manipulation of cell lines by CRISPR and RNAi, lentivirus production, etc
Biochemistry: Protein purification, protein-protein interaction assays such as pulldowns and immunoprecipitations, immunoblotting, enzymatic assays, etc
Leyme A et al. Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein. Proceedings of the National Academy of Sciences USA (PNAS). 2017 Nov 28;114(48):E10319-E10328. doi: 10.1073/pnas.1707992114. Epub 2017 Nov 13.
DiGiacomo V, et al. When Heterotrimeric G Proteins Are Not Activated by G Protein-Coupled Receptors: Structural Insights and Evolutionary Conservation. 2018 Jan 23;57(3):255-257. doi: 10.1021/acs.biochem.7b00845. Epub 2017 Oct 16. – MINI-REVIEW
de Opakua AI, et al. Molecular mechanism of Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif. Nature Communications. 2017 May 18;8:15163. doi: 10.1038/ncomms15163.
Parag-Sharma K, et al. Membrane Recruitment of the Non-receptor Protein GIV/Girdin (Galpha-interacting, Vesicle-associated Protein/Girdin) Is Sufficient for Activating Heterotrimeric G Protein Signaling. Journal of biological chemistry. Dec 30;291(53):27098-27111. PMID: 27864364
Marivin A. et al. Dominant negative Gα subunits as a novel mechanism of trimeric G protein signaling dysregulation in human disease. Science Signaling. Apr 12;9(423):ra37. PMID: 27072656.
Leyme A. Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin. Journal of Cell Biology. 2015 Sep 28;210(7):1165-84. PMID: 26391662.
Aznar N, et al. Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. Elife. 2015 Jun 30;4:e07091. PMID: 26126266
Garcia-Marcos M. et al. GIV/ Girdin transmits signals from multiple receptors by triggering trimeric G protein activation. Journal of Biological Chemistry. 2015. Mar 13;290(11):6697-704. PMID: 25605737.- MINI-REVIEW
The requirement have been described in the "Description" section.